POS0236 SAFETY AND EFFICACY OF NEUROSTIMULATION WITH A MINIATURIZED VAGUS NERVE STIMULATION DEVICE IN PATIENTS WITH MULTIDRUG-REFRACTORY RHEUMATOID ARTHRITIS: 24-WEEK FOLLOW-UP OF A RANDOMIZED CONTROLLED FIRST-IN-HUMAN TRIAL
Authors: N. Gaylis, M. C. Genovese, D. Sikes, A. Kivitz, D. M. Horowitz, C. Peterfy, Y. Levine, M. Evangelista, D. Chernoff
Journal: Annals of the Rheumatic Diseases (2022)

Background Vagus nerve stimulation (VNS) activates innate neuroimmune reflexes that have been shown to reduce pro-inflammatory cytokines and clinical disease activity in subjects with rheumatoid arthritis (RA) .1 We previously reported primary clinical outcomes from a first-in-human, double-blind study of a novel, implanted VNS device called a MicroRegulator (MR). That study showed 5/10 subjects with drug-refractory RA met or exceeded the minimal clinically important difference (MCID) in DAS28-CRP; 2 subjects achieved DAS28 remission (DAS28-CRP &lt; 2.6); and pro-inflammatory cytokines were decreased by &gt;30% following 12 weeks of VNS. 2 We now report 24-week efficacy and safety findings from this study. Objectives Determine the long-term safety and exploratory efficacy of neurostimulation using a novel, miniaturized VNS device in patients with multiple drug refractory RA who were previously enrolled in a first in human study. Methods The primary study enrolled adult patients with active moderate-to-severe RA with incomplete response or intolerability to at least two biologic and/or targeted synthetic DMARDs having at least two different mechanisms of action. The study was enrolled in 2 Stages: Stage 1 (n=3) was open-label, and Stage 2 (n=11) was randomized and sham-controlled (Figure 1). Three weeks after MR implantation, the first 3 subjects in Stage 1 received active VNS for 1 minute, once per day (QD). Following safety review board approval, 11 patients in Stage 2 were implanted with the MR and randomized 1:1:1 into one of two active VNS groups (1 minute of VNS QD or 1 minute of active VNS four times per day [QID]) or a sham group. At Week 12, the blind was lifted, sham subjects were re-randomized and crossed over to either QD or QID active VNS dosing, and all actively treated subjects remained on their dosing through Week 24. Safety and tolerability were determined, and several secondary efficacy endpoints were evaluated measuring the change in disease activity from the start of active VNS to Week 24. Figure 1. Study Schematic Results There were no device-related adverse events from Week 12 through Week 24. Improvement in clinical disease activity was sustained through Week 24: 5/9 patients within the original, active VNS treatment groups met or exceeded EULAR response criteria for DAS28-CRP at Week 24 (Table 1) vs. 5/10 at Week 12 (one Week 12 responder was lost to follow-up). Similarly, 6/9 patients in the original, active VNS treatment groups met or exceeded the MCID in CDAI at Week 24 vs. 5/10 at Week 12. In the long-term extension, 1/4 sham crossover patients had both EULAR and CDAI response after 12 weeks of VNS (1/2 QD, 0/2 QID). Co-therapy with a b/tsDMARD was initiated in 2 subjects (Table 1). One crossover subject was treated with oral methylprednisolone at week 19 due to worsening RA disease activity. VECTRA composite scores and component analysis revealed an 18-point decrease in median multi-analyte disease activity index in the QD group over 24 weeks of VNS with a decrease in serum levels of several analytes in key component categories (IL-6, serum amyloid A, and VCAM-1). Erosion progression by hand MRI was stabilized or decreased in all but 1 of the stimulated patients at Week 24. Table 1. Change in DAS28-CRP at Week 24 Subject Treatment DAS28-CRP (MCID -1.2) *added b/tsDMARD co-therapy 005-01 QD -2.4 005-03 QD -2.21 006-01 QD -0.07 002-01 QD -4.95 * 005-06 QD -0.72 * 006-03 QID -0.69 008-01 QID 0.49 008-03 QID -3.14 008-04 QID 1.43 005-05 Sham to QD 0.39 006-04 Sham to QD -0.78 006-02 Sham to QID -0.22 008-02 Sham to QID -0.09 Conclusion Improvements in clinical disease activity and pro-inflammatory cytokine suppression were maintained through 24 weeks of VNS treatment. Safety outcomes continue to support the risk/benefit profile of VNS as a treatment option for patients with multiple-drug refractory RA. References [1]Koopman PNAS 2016 [2]Genovese et al. Lancet Rheum 2020. Acknowledgements Authors wish to thank the patients for participating in the study Disclosure of Interests Norman Gaylis Grant/research support from: Primary investigator at AARDS Research Inc, Mark C. Genovese Shareholder of: Gilead Sciences, Consultant of: SetPoint Medical Inc, Vorso, InMedix, Galvani, Employee of: Gilead Sciences, David Sikes: None declared, Alan Kivitz Shareholder of: Amgen, Gilead, GSK, Sanofi, Pfizer, Speakers bureau: Abbvie, Celegene, Pfizer, Horizon, Merck, Genzyme, Sanofi, Flexion, Paid instructor for: Abbvie, Celegene, Pfizer, Horizon, Merck, Genzyme, Sanofi, Flexion, Consultant of: Abbvie, Janssen, Pfizer, Genzyme, Sanofi, Regeneron, Sun Pharma, Boehringer Ingelheim, Gilead, Diane M Horowitz: None declared, Charles Peterfy Speakers bureau: Amgen, Bristol-Myers Squibb, Consultant of: Abbvie, Five Prime, Genentech, Modern Bioscience, Myriad, Novartis, Roche, SetPoint Medical, Vorso, Employee of: Spire Sciences Inc, Yaakov Levine Employee of: Setpoint Medical, Melissa Evangelista Employee of: SetPoint Medical, David Chernoff Employee of: SetPoint Medical